Our purpose is to examine the acute and chronic responses of the pulmonary endothelium of rats and mice to three clinically relevant forms of lung injury: (1) ionizing radiation (delivered as 1, 2, 5, or 10 fractions of 60Co Gamma-rays), (2) monocrotaline ingestion, and (3) bleomycin injections. The acute responses of endothelial cells to injury in situ will be compared with those observed in endothelial monolayers in vitro. Endothelial histology and ultrastructure will be quantitated morphometrically, and will be correlated with four indices of endothelial function: (1) angiotensin converting enzyme (ACE) activity, (2) plasminogen activator (PLA) activity, (3) prostacyclin (PGI2) production, and (4) thromboxane (TXA2) production. ACE, PLA, PGI2 and TXA2 levels in the bronchoalveolar lavage fluid also will be determined. Structural and functional changes in the endothelium will be related to organ function, as demonstrated by pulmonary arterial perfusion scans, and to the anatomic correlates of pulmonary hypertension, i.e. hepato- and cardiomegaly, right heart enlargement, and pulmonary arterial wall thickening. Mechanisms of pulmonary injury at the cellular level will be examined by (1) differential cytology of the lung as determined from histology, ultrastructure, and fluorescence-activated cell sorting of trypsinized lung cell populations at various times after injury, and (2) differential responses of cultured vascular endothelial cells, smooth muscle cells, and fibroblasts in vitro to the three insults. Fluorescein- and peroxidase-labeled ACE antibody binding will be employed to measure the number of endothelial cells in the irradiated lung as a function of time, dose and fractionation. This may clarify the relationship between cell survival and organ function with respect to the pulmonary endothelium. Finally, the ability of the following agents to modify the pathogenesis of endothelial injury in vivo and in vitro will be determined: (1) ACE inhibitors (Captopril, CL242817); (2) PGI2 analogues (CL115347); and (3) antiinflammatories (indomethacin, prenisolone, and penicillamine). These data may identify mechanisms of pulmonary injury, particularly the role of endothelial damage therein, and may reveal steps at which intervention in the pathogenesis of lung injury may be accomplished in a clinically significant manner.